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Children
And Leukemia
Why Do Some Forms of Leukemia Affect Mostly Children?
By Nicoletta Lanese - Staff
Writer
Childhood leukemias may exploit specific vulnerabilities found
only in immature cells.
Certain forms of leukemia tend to strike early in life and
affect far more children than adults.
Leukemia, which disrupts normal cell growth in the blood and bone
marrow, accounts for nearly one-third of all childhood cancer cases, according
to the American Cancer Society (ACS).
The disease manifests in various forms, and the subtypes that
mostly affect children typically progress quickly and require immediate,
aggressive treatment.
Although similarities exist between childhood and adult
leukemias, evidence suggests that the cancers don't share the same genetic
roots.
"What has been known for some
time is that there are clear genetic differences
between childhood cancer and adult cancer," said Dr. Thomas
Mercher, a director of hematology-oncology research for the French National
Institute of Health and Medical Research and the Gustave Roussy research
institute in Villejuif, France.
Studies suggest that the specific
genetic quirks seen in childhood leukemia cells may arise very early in life,
or even in the womb, but how this happens step by step "is
generally very unclear," Mercher said.
Now, new research hints that childhood leukemia may be able to hijack only young,
developing cells — like those found in fetuses and children — not the mature
cells of full-grown adults.
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To investigate why certain leukemias may prey on immature cells, Mercher and his colleagues gathered genetic samples from young patients with a particularly aggressive form of acute myeloid leukemia (AML) and replicated the disease in mouse models.
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To investigate why certain leukemias may prey on immature cells, Mercher and his colleagues gathered genetic samples from young patients with a particularly aggressive form of acute myeloid leukemia (AML) and replicated the disease in mouse models.
The team's study, published Oct. 29 in the journal Cancer Discovery, hints at why the cancer appears early
in life, often before the affected child reaches 2 years old.
"The genetic alterations that we
studied here are only found in childhood leukemia," Mercher added.
In general, AML is more prevalent in adults than children; the
disease accounts for fewer than 25% of all childhood leukemia cases, according
to the American Cancer Society.
However, a rare subtype called "acute myeloblastic leukemia
type 7" (AML-M7) predominantly appears in infants under the age of 2.
Children with other forms of AML develop the disease later in
life, around age 6, and show better survival rates than individuals with the
more-aggressive subtype, the authors noted in a statement.
Could the children's ages at the time of disease onset offer
clues as to why these cancers have such different outcomes? To find out, the
researchers looked to the children's genes.
Frankenstein-style mutations
Back in 2012, the team gathered leukemia cells from both
children and adults who had AML-M7, discovering a key difference between the
genetic material in the children versus the adults.
Many of the children's cells contained genes that had merged
together, Frankenstein-style, to form new, hybrid genes.
Individually, the genes play important roles in blood cell
development, but once stuck together, those genes may direct cells to build
unusual proteins and ultimately transform into cancerous cells, the researchers
theorized.
None of these "fusion genes" appeared in a single
adult leukemia cell, which hinted that the team might be onto something.
After the researchers published this initial finding, they and other scientists found ample evidence of fusion genes in AML-M7 leukemia.
But no one knew exactly what these hybrid genes did or why they
appeared only in children.
So, Mercher and his colleagues continued to investigate,
focusing their research on a fusion gene known as ETO2–GLIS2.
Welding together two normally separate genes, ETO2 and GLIS2,
the mutation appears in about 30% of children with AML-M7 and seems linked to
poor responses to cancer treatment and low survival rates, the researchers
wrote.
To learn how this mutation drives cancer, the team observed how
the fusion gene seized control of hematopoietic stem cells, cells that normally give rise to healthy
blood cells but can get hijacked by leukemia.
The scientists developed a mouse model in which they could turn
the ETO2–GLIS2 mutation "on" or "off" in a given tissue
inside the mouse.
They ran their experiment in both fetal and adult-age mice to
see if the fusion gene would affect cells differently depending on the cells'
stage of development.
Turns out, that's exactly what happened. When the team activated
ETO2–GLIS2 in fetal stem cells, the resulting proteins seemed to tamper with
cellular pathways that normally turn the cells into healthy blood cells.
Basically, the fusion gene flipped a "molecular
switch" that rapidly transformed the stem cells into aggressive leukemia.
Blocking ETO2–GLIS2 activation in the same fetal mice flipped
the switch back, curbed the cancer growth and allowed stem cells to turn into
normal blood once more.
By comparison, the adult stem cells appeared "much less
prone to give rise to leukemia" when ETO2–GLIS2 was activated, Mercher
said.
In fact, the fusion gene did not appear to be a key driver of
leukemia progression in adult mice.
"The developmental stage of the
cells in which the mutation arises determines the aggressiveness and the type
of leukemia that you get," Mercher said.
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The results "show that more people should be paying attention to the fetal bone marrow environment," where hematopoietic stem cells can be found, said Dr. Mignon Loh, a pediatric hematologist-oncologist at the University of California, San Francisco, who was not involved in the study.
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The results "show that more people should be paying attention to the fetal bone marrow environment," where hematopoietic stem cells can be found, said Dr. Mignon Loh, a pediatric hematologist-oncologist at the University of California, San Francisco, who was not involved in the study.
The immediate environment, or niche, where a fetal stem cell
develops looks very different from the environment surrounding an adult cell,
she said.
"When you're a baby and have
been incubating for 9 months, that niche is pretty pure," Loh said.
Important distinctions between childhood and adult leukemia may lie in how the
bone marrow functions in people of different ages and how cancer commandeers
that tissue for its own purposes, she said.
Research into ETO2–GLIS2 may also shed light on how other forms
of childhood leukemia rely on fusion genes, provided that the team's findings
in mice hold true in humans, Loh said.
More broadly, further research into the nature of fetal stem
cells in general could reveal other avenues by which leukemia exploits
developing cells, she said.
"There may be something
permissive about a fetal-like stem cell" that allows it to transform into
malignant cancer, Loh said.
If future research could pinpoint how child-specific mutations
cause leukemia, drugs could be developed to stall or stop the disease, Mercher
added.
"That would be like [finding]
the holy grail," Loh said.
Nicoletta
Lanese
is a science journalist and dancer who aims to bring science to new audiences,
whether in print or on stage. She holds degrees in neuroscience and dance from
the University of Florida and a graduate certificate in science communication
from the University of California, Santa Cruz. Brains are her beat. Follow her
on Twitter @NicolettaML.
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